Summary of project + methods

This study is examining the association between DNA methylation and childhood eczema (up to ~10 years). Studies have data from different timepoints, so in the first instance we will classify individuals as ‘any eczema’ versus ‘no eczema’ according to all timepoints available up to age 10. Sub-analyses will be conducted that limits cases to those children who are diagnosed early in childhood (by ~2 years) or have persistent eczema (diagnosed by age 2 and have current eczema at age 8yrs).

The analyses will therefore use 3 binary definitions:

  • Childhood AD - cases: AD by age 10, controls:no AD by age 10
  • Early-onset AD - cases: AD by age 2, controls: no AD by age 2
  • Persistent AD - cases: AD by age 2 and persisting to ~ 8-10yrs, controls: no AD by age 10

The association of each outcome with DNA methylation will be explored using logistic regression and 3 models with different covariates:

  • model a: sex + batch (+ selection_factors) (+ ancestry)
  • model b: sex + batch + maternal_age + maternal_smoking + maternal_SES + gestational_age (+selection_factors) (+ ancestry)
  • model c: sex + batch + maternal_age + maternal_smoking + maternal_SES + gestational_age + cell_type (+ selection_factors) (+ ancestry)

See results of the meta-analyses using each AD definition and model below.

Childhood AD

Samplesizes

cohort N N_cases N_controls prevalence
ALSPAC 673 343 330 50.965825
CHS 197 50 147 25.380711
EDEN 153 69 84 45.098039
GENR 450 69 381 15.333333
INMA 462 216 246 46.753247
MoBa1 831 399 432 48.014440
MoBa2 418 179 239 42.822966
NEST_B 77 56 21 72.727273
NEST_W 41 22 19 53.658537
PREDO 792 54 738 6.818182
VITO 78 23 55 29.487179
GOYA 517 93 424 17.988395
IOW 616 179 437 29.058442
Total 5305 1752 3553 33.025448

QQ

manhattan

top hits

CpG Gene Chr BP Beta SE P FDR_P Direction Isq Het_p
model a
cg03030757 FANCE 6 35,420,754 -5.8e+00 1.206 1.7e-06 0.42 –+———- 0.0 7.4e-01
cg03738669 SLC4A11 20 3,218,476 -3.2e+00 0.674 2.6e-06 0.42 –+—-++-+– 30.9 1.4e-01
cg00888758 HRNR 1 152,196,674 -3.3e+00 0.713 2.9e-06 0.42 ———-+– 0.0 9.1e-01
cg09768093 ZBTB8B 1 32,930,511 -1.9e+01 4.117 4.4e-06 0.47 ——–+–+- 0.0 8.3e-01
cg03303325 TBCD 17 80,823,240 4.3e+00 0.983 1.1e-05 0.66 ++++++++++–+ 0.0 8.4e-01
cg09730123 SPSB3 16 1,827,948 -3.7e+00 0.856 1.4e-05 0.66 ——–+-++- 0.0 4.5e-01
cg10142520 EHBP1L1 11 65,344,604 -3.1e+00 0.717 1.4e-05 0.66 ———–+- 23.6 2.0e-01
cg00564723 CAMK2G 10 75,632,066 -4.5e+00 1.042 1.6e-05 0.66 –+—–+—- 0.0 8.5e-01
cg27021553 CCND1 11 69,462,783 -3.0e+00 0.705 2.1e-05 0.66 —–+—–+- 0.0 7.2e-01
cg14011244 11 130,240,665 -2.5e+00 0.588 2.2e-05 0.66 –++—–++– 28.3 1.6e-01
model b
cg19317715 AOC2 17 40,996,578 -2.8e+00 0.59 2.0e-06 0.32 ———-+– 0.0 6.9e-01
cg03030757 FANCE 6 35,420,754 -5.9e+00 1.26 2.5e-06 0.32 –+———- 0.0 6.5e-01
cg00888758 HRNR 1 152,196,674 -3.4e+00 0.73 2.5e-06 0.32 ——–+-+– 0.0 8.0e-01
cg09730123 SPSB3 16 1,827,948 -4.1e+00 0.88 3.0e-06 0.32 ——–+-++- 0.0 4.6e-01
cg03303325 TBCD 17 80,823,240 4.6e+00 1.02 6.2e-06 0.51 ++++++++++–+ 0.0 7.1e-01
cg18028767 TSPAN4 11 859,873 -4.6e+00 1.02 7.7e-06 0.51 -+——–+-? 0.0 6.4e-01
cg03738669 SLC4A11 20 3,218,476 -3.1e+00 0.71 9.1e-06 0.51 –+—-++—- 30.9 1.4e-01
cg20762346 6 168,619,344 4.2e+00 0.96 1.2e-05 0.51 ++++++++-+++? 0.0 6.1e-01
cg11772801 TMX1 14 51,711,237 -3.6e+00 0.82 1.2e-05 0.51 ————- 0.0 5.5e-01
cg18560936 7 1,632,620 2.5e+00 0.58 1.2e-05 0.51 ++++-++++++++ 0.0 8.2e-01
model c
cg11772801 TMX1 14 51,711,237 -4.3e+00 0.93 4.3e-06 1 —+——– 11.4 3.3e-01
cg00888758 HRNR 1 152,196,674 -3.5e+00 0.80 1.0e-05 1 ———+– 0.0 9.0e-01
cg04164048 IL34 16 70,680,498 5.6e+00 1.31 2.0e-05 1 +++++++-+-++ 0.0 9.8e-01
cg03738669 SLC4A11 20 3,218,476 -3.1e+00 0.74 2.9e-05 1 –+–+-+—- 46.4 3.9e-02
cg19317715 AOC2 17 40,996,578 -2.7e+00 0.66 3.4e-05 1 –+——+– 0.0 6.3e-01
cg13917287 SLC15A1 13 99,401,109 -6.6e+00 1.58 3.4e-05 1 —-+–+—? 32.3 1.4e-01
cg21953146 MAPT 17 44,061,258 -4.0e+00 0.98 3.9e-05 1 —-+—?+– 0.0 6.7e-01
cg20330126 APOL5 22 36,125,053 -4.9e+00 1.20 4.5e-05 1 ———-+- 23.0 2.2e-01
cg19668951 SLC39A13 11 47,430,812 -4.1e+00 1.02 5.1e-05 1 -+——–+- 0.0 7.3e-01
cg00564723 CAMK2G 10 75,632,066 -4.5e+00 1.11 5.4e-05 1 –+——+– 0.0 9.6e-01

Early-onset AD

Samplesizes

cohort N N_cases N_controls prevalence
ALSPAC 667 169 498 25.337331
CHS 197 41 156 20.812183
DCHS 266 26 240 9.774436
EDEN 142 48 94 33.802817
GENR 742 171 571 23.045822
INMA 348 83 265 23.850575
IOW-F2 171 28 143 16.374269
MoBa1 993 361 632 36.354481
MoBa2 386 210 176 54.404145
NEST_B 119 30 89 25.210084
UKIDS 607 216 390 35.584843
VITO 70 15 55 21.428571
GOYA 517 39 478 7.543520
IOW 667 99 569 14.842579
Total 5892 1536 4356 26.069246

QQ

manhattan

top hits

CpG Gene Chr BP Beta SE P FDR_P Direction Isq Het_p
model a
cg26014373 OLFML2A 9 127,572,640 8.8e+00 1.77 7.2e-07 0.26 +++++++++-+-+? 0.0 9.0e-01
cg19768607 11 68,768,879 1.0e+01 2.16 1.2e-06 0.26 +-++++++-++-++ 2.1 4.3e-01
cg18372960 SDK1 7 4,305,728 -2.9e+00 0.62 2.3e-06 0.32 ———+—- 0.0 8.5e-01
cg13863007 FGD3 9 95,766,607 -3.7e+00 0.81 5.0e-06 0.39 —–++——- 0.0 7.2e-01
cg00340921 PNPLA6 19 7,600,526 -1.1e+01 2.49 5.2e-06 0.39 –+-+——-+- 0.0 7.3e-01
cg14833040 6 47,197,781 8.8e+00 1.95 5.6e-06 0.39 +++++++++++-++ 0.0 5.8e-01
cg00631837 PHF21B 22 45,404,212 -6.7e+00 1.51 1.0e-05 0.51 —-++—–++- 0.0 6.8e-01
cg10154010 ABCA3 16 2,326,080 7.8e+00 1.78 1.1e-05 0.51 ++++++++-+++++ 0.0 4.6e-01
cg24652615 TMEM151B 6 44,243,304 -1.3e+00 0.30 1.2e-05 0.51 -+——–+— 0.0 6.0e-01
cg26782881 MPP2 17 41,977,585 -5.1e+00 1.16 1.3e-05 0.51 ———+—- 0.0 9.1e-01
model b
cg26014373 OLFML2A 9 127,572,640 8.9e+00 1.77 4.6e-07 0.20 +++++++++-+-+? 0.0 9.1e-01
cg19768607 11 68,768,879 1.1e+01 2.18 1.4e-06 0.30 +-++++++–+-++ 0.0 4.6e-01
cg00340921 PNPLA6 19 7,600,526 -1.2e+01 2.52 5.1e-06 0.48 –+-+——-+- 0.0 7.9e-01
cg14833040 6 47,197,781 8.9e+00 1.96 5.1e-06 0.48 ++++++++++++++ 0.0 5.9e-01
cg18372960 SDK1 7 4,305,728 -2.8e+00 0.62 5.6e-06 0.48 —-+—-+—- 0.0 6.4e-01
cg10154010 ABCA3 16 2,326,080 7.9e+00 1.78 1.1e-05 0.59 ++++++++++++++ 0.0 4.7e-01
cg00447469 TFDP1 13 114,251,707 1.0e+01 2.30 1.1e-05 0.59 ++++++-+-+++++ 0.2 4.5e-01
cg00631837 PHF21B 22 45,404,212 -6.8e+00 1.54 1.1e-05 0.59 —-+——++- 0.0 8.1e-01
cg15275393 PARK2 6 162,067,688 -2.8e+00 0.66 1.5e-05 0.62 –?–++—-+– 0.0 8.8e-01
cg22063269 WBSCR16 7 74,489,892 1.0e+01 2.32 1.7e-05 0.62 ++-+++?+-++-+- 11.1 3.3e-01
model c
cg26014373 OLFML2A 9 127,572,640 9.9e+00 1.92 2.5e-07 0.11 ++–+++++++++? 0.0 9.4e-01
cg19768607 11 68,768,879 1.3e+01 2.56 5.5e-07 0.12 ++++++++-++-++ 0.0 8.5e-01
cg14833040 6 47,197,781 9.6e+00 2.10 5.1e-06 0.45 ++-+++++++++++ 0.0 7.6e-01
cg02872868 SORBS2 4 186,565,192 -3.5e+00 0.76 5.6e-06 0.45 —–++-+–+– 0.0 6.0e-01
cg18372960 SDK1 7 4,305,728 -3.0e+00 0.65 5.9e-06 0.45 —-+—-+—- 0.0 5.8e-01
cg19856241 4 148,233,162 8.3e+00 1.84 6.9e-06 0.45 +++++++++++–+ 0.0 5.8e-01
cg27139419 IGF1R 15 99,212,404 -3.1e+00 0.68 7.5e-06 0.45 –+–+——-? 14.7 3.0e-01
cg24098008 10 132,877,018 -4.7e+00 1.08 1.4e-05 0.63 –?—?–+?+-? 0.0 7.0e-01
cg15275393 PARK2 6 162,067,688 -3.0e+00 0.70 1.5e-05 0.63 –?–++—-+– 0.0 8.4e-01
cg22063269 WBSCR16 7 74,489,892 1.1e+01 2.46 1.7e-05 0.63 ++-+++?+-++-+- 14.0 3.0e-01

Persistent AD

Samplesizes

cohort N N_cases N_controls prevalence
ALSPAC 662 125 537 18.882175
CHS 197 35 162 17.766497
EDEN 126 18 108 14.285714
GENR 415 39 376 9.397590
MoBa1 519 87 432 16.763006
MoBa2 237 61 176 25.738397
VITO 66 11 55 16.666667
GOYA 517 33 484 6.382979
IOW 462 25 437 5.411255
Total 3201 434 2767 13.558263

QQ

manhattan

top hits

CpG Gene Chr BP Beta SE P FDR_P Direction Isq Het_p
model a
cg02716826 SUGT1P1 9 33,447,032 -6.6e+00 1.39 1.7e-06 0.39 –+—— 0.0 9.0e-01
cg19322065 1 37,701,025 -3.7e+00 0.79 3.2e-06 0.39 ——— 0.0 9.8e-01
cg03723730 GRM4 6 34,031,694 -7.6e+00 1.63 3.3e-06 0.39 –+—— 0.0 4.5e-01
cg10143807 EFNA3 1 155,050,924 1.4e+01 3.03 4.1e-06 0.39 ++-++-+++ 0.0 4.9e-01
cg20330126 APOL5 22 36,125,053 -7.4e+00 1.62 5.6e-06 0.39 ——-+- 0.0 6.5e-01
cg24877842 TRAK1 3 42,201,898 -6.4e+00 1.42 6.1e-06 0.39 ——— 0.0 9.6e-01
cg11794356 OR6C3 12 55,725,991 -4.5e+00 1.00 7.2e-06 0.39 -+——- 0.0 8.4e-01
cg05233310 PRSS27 16 2,765,900 -7.6e+00 1.70 7.3e-06 0.39 -+——- 0.0 9.3e-01
cg00276389 TMPRSS6 22 37,466,935 -7.7e+00 1.79 1.4e-05 0.61 ——— 0.0 5.2e-01
cg02538891 9 139,549,426 -8.3e+00 1.91 1.4e-05 0.61 ——— 0.0 6.4e-01
model b
cg19322065 1 37,701,025 -3.7e+00 0.80 3.2e-06 0.49 ——— 0.0 9.7e-01
cg05233310 PRSS27 16 2,765,900 -8.0e+00 1.72 3.8e-06 0.49 -+——- 0.0 9.0e-01
cg03723730 GRM4 6 34,031,694 -7.7e+00 1.66 3.9e-06 0.49 –+—— 0.0 6.0e-01
cg10143807 EFNA3 1 155,050,924 1.4e+01 3.14 5.6e-06 0.49 +++++-+++ 0.0 5.8e-01
cg02716826 SUGT1P1 9 33,447,032 -6.5e+00 1.44 6.5e-06 0.49 –+—— 0.0 6.7e-01
cg11794356 OR6C3 12 55,725,991 -4.5e+00 1.01 9.9e-06 0.49 -+——- 0.0 8.2e-01
cg24877842 TRAK1 3 42,201,898 -6.4e+00 1.46 9.9e-06 0.49 ——— 0.0 8.9e-01
cg14150666 CXCR2 2 218,991,310 -4.2e+00 0.96 1.1e-05 0.49 –+—+– 0.0 7.6e-01
cg00276389 TMPRSS6 22 37,466,935 -8.0e+00 1.82 1.1e-05 0.49 ——— 0.0 6.1e-01
cg27018461 PCCB 3 135,969,916 -7.5e+00 1.70 1.1e-05 0.49 —+–+– 39.7 1.0e-01
model c
cg05233310 PRSS27 16 2,765,900 -8.7e+00 1.81 1.6e-06 0.54 ——— 0.0 9.2e-01
cg19322065 1 37,701,025 -3.8e+00 0.83 4.2e-06 0.54 ——— 0.0 9.8e-01
cg20330126 APOL5 22 36,125,053 -8.7e+00 1.90 4.4e-06 0.54 ——++- 43.4 7.9e-02
cg14150666 CXCR2 2 218,991,310 -5.0e+00 1.09 5.5e-06 0.54 –+—+– 0.0 7.9e-01
cg02716826 SUGT1P1 9 33,447,032 -7.4e+00 1.64 7.5e-06 0.54 –+—+– 0.0 5.1e-01
cg17504584 IQCC 1 32,671,645 -2.6e+01 5.82 8.3e-06 0.54 +——-? 0.0 6.7e-01
cg10143807 EFNA3 1 155,050,924 1.5e+01 3.36 9.0e-06 0.54 +++++-+++ 19.6 2.7e-01
cg13280041 NHSL1 6 138,866,865 -5.0e+00 1.14 1.1e-05 0.58 ——+– 0.0 9.1e-01
cg09903452 SEPT9 17 75,315,244 -7.8e+00 1.78 1.3e-05 0.61 –+—–+ 27.5 2.0e-01
cg00276389 TMPRSS6 22 37,466,935 -8.2e+00 1.90 1.7e-05 0.62 ——— 0.0 4.6e-01

Correlation between models